Cilium induction triggers differentiation of glioma stem cells.

Gladiola Goranci-Buzhala,Brian Dynlacht,Simone Pacioni,Marco Gottardo,Johannes Ptok,Krishnaraj Rajalingam,Natasa Josipovic,Lucia Ricci-Vitiani,Heiner Schaal,Jay Gopalakrishnan,Aruljothi Mariappan,Giuliano Callaini,Argyris Papantonis,Kamyar Hadian,Roberto Pallini

doi:10.1016/j.celrep.2021.109656

Gladiola Goranci-Buzhala, Brian Dynlacht + Show 13 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109656

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Abstract

Glioblastoma multiforme (GBM) possesses glioma stem cells (GSCs) that promote self-renewal, tumor propagation, and relapse. Understanding the mechanisms of GSCs self-renewal can offer targeted therapeutic interventions. However, insufficient knowledge of GSCs' fundamental biology is a significant bottleneck hindering these efforts. Here, we show that patient-derived GSCs recruit elevated levels of proteins that ensure the temporal cilium disassembly, leading to suppressed ciliogenesis. Depleting the cilia disassembly complex components is sufficient to induce ciliogenesis in a subset of GSCs via relocating platelet-derived growth factor receptor-alpha (PDGFR-α) to a newly induced cilium. Importantly, restoring ciliogenesis enabled GSCs to switch from self-renewal to differentiation. Finally, using an organoid-based glioma invasion assay and brain xenografts in mice, we establish that ciliogenesis-induced differentiation can prevent the infiltration of GSCs into the brain. Our findings illustrate a role for cilium as a molecular switch in determining GSCs' fate and suggest cilium induction as an attractive strategy to intervene in GSCs proliferation.

Highlights

Glioblastoma (GBM) is the most frequent malignant primary brain tumor (Matsukado et al, 1961; Ostrom et al, 2014; Ferreri et al, 2010)
We show that patient-derived glioma stem cells (GSCs) recruit elevated levels of proteins that ensure the temporal cilium disassembly, leading to suppressed ciliogenesis
Restoring ciliogenesis enabled GSCs to switch from self-renewal to differentiation

Summary

Introduction

Glioblastoma (GBM) is the most frequent malignant primary brain tumor (Matsukado et al, 1961; Ostrom et al, 2014; Ferreri et al, 2010). Low passage patient-derived glioma stem cells (GSCs) are phenotypically similar to in vivo tumors characterized by their self-renewal and multi-lineage differentiation (Singh et al, 2003; Jacob et al, 2020; Pine et al, 2020, Wang et al, 2019; Lathia et al, 2015). GSCs possess neural stem cell attributes exhibiting uncontrolled self-renewal properties This could be due to genetic alterations in GSCs, adaptation between proliferative and slow-cycling states, and enrichment of stemness on therapy (Liau et al, 2017; Park et al, 2017; Ricci-Vitiani et al, 2010; Rajakulendran et al, 2019; Neftel et al, 2019; Wang et al, 2019). Intense efforts are being made to understand the mechanisms of GSCs proliferation that can be exploited for therapeutic interventions

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